Computational Models of Ventricular- and Atrial-Like Human Induced Pluripotent Stem Cell Derived Cardiomyocytes

Abstract

The clear importance of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) as an in-vitro model highlights the relevance of studying these cells and their function also in-silico. Moreover, the phenotypical differences between the hiPSC-CM and adult myocyte action potentials (APs) call for understanding of how hiPSC-CMs are maturing towards adult myocytes. Using recently published experimental data, we developed two computational models of the hiPSC-CM AP, distinguishing between the ventricular-like and atrial-like phenotypes, emerging during the differentiation process of hiPSC-CMs. Also, we used the computational approach to quantitatively assess the role of ionic mechanisms which are likely responsible for the not completely mature phenotype of hiPSC-CMs. Our models reproduce the typical hiPSC-CM ventricular-like and atrial-like spontaneous APs and the response to prototypical current blockers, namely tetrodotoxine, nifedipine, E4041 and 3R4S-Chromanol 293B. Moreover, simulations using our ventricular-like model suggest that the interplay of immature I Na, I f and I K1 currents has a fundamental role in the hiPSC-CM spontaneous beating whereas a negative shift in I CaL activation causes the observed long lasting AP. In conclusion, this work provides two novel tools useful in investigating the electrophysiological features of hiPSC-CMs, whose importance is growing fast as in-vitro models for pharmacological studies.

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

“…The result is that current mathematical AP models of hPSC‐CMs (Paci et al , 2013, 2015, 2012) still represent a fraction of the heterogeneity that has been experimentally observed in literature, although their usefulness and predictivity are beyond doubt (Figure 3). In this context, the coordination and promotion of standard methodologies for phenotypic characterization of differentiated cells may come from cell banks.…”

“…Computational models for ion currents are being generated based on existing electrophysiological data measured in adult animal/human CMs as well as hPSC‐CMs and then integrated into complex single‐ or multi‐cellular models (O'Hara et al , 2011; Paci et al , 2013). It is expected that, as computational power increases, the accuracy and complexity of such models will rise.…”

“…It is expected that, as computational power increases, the accuracy and complexity of such models will rise. However, the heterogeneity of hiPSC‐CM phenotypes may limit the predictive power of current models (Paci et al , 2013, 2015). For example, different differentiation protocols lead to different ventricular phenotypes (Figure 3), integrating reprogramming methods may disrupt genes of interest for the phenotype under study, and the kinetics of hiPSC‐CM differentiation may differ between individual lines.…”

Population-Based Mechanistic Modeling Allows for Quantitative Predictions of Drug Responses across Cell Types

“…Although many alternative mathematical models of animal myocytes 35,36 and human adult ventricular myocytes 37,38 have been published, the Paci et al model 14 remains, at the present time, the only model of the iPSC-CM. The preferred approach to modeling iPSC-CM physiology will certainly be modified as additional data become available, and as iPSC-CMs developed under particular conditions become more completely characterized.…”

“…11,12 To extend these ideas, we attempted to translate drug responses from iPSC-CMs to human adult ventricular myocytes. Beginning with mathematical models of two cell types, 13,14 we combined simulations of heterogeneous populations with multivariable regression approaches. The resulting model could be used to predict, with quantitative accuracy, drug effects in human adult myocytes based on recordings in iPSC-CMs.…”